Elucidating the Mechanisms Mediating the Impact of Neuroactive Steroids on Network and Behavioral States

阐明神经活性类固醇对网络和行为状态影响的调节机制

• 批准号: 10456975
• 负责人: Jamie Lynn Maguire
• 金额: $ 54.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456975
• 关键词: Acute; Affective; Allopregnanolone; Amygdaloid structure; Animal Model; Anti-Anxiety Agents; Antidepressive Agents; Behavioral; Brain; Brain region; CRISPR/Cas technology; Chemistry; Chronic; Clinical; Clinical Trials; Collaborations; Communication; Data; Drug Utilization; Formulation; Generations; Goals; Hippocampus (Brain); Human; Interneurons; Intravenous; Knock-out; Knowledge; Link; Medial; Mediating; Mental disorders; Modeling; Mood Disorders; Nature; Neurons; Parvalbumins; Patients; Play; Postpartum Depression; Postpartum Period; Pre-Clinical Model; Prefrontal Cortex; Property; Psychiatric therapeutic procedure; Research Support; Risk Factors; Role; SWI1; Site; Stress; Techniques; Testing; Therapeutic; antidepressant effect; base; behavior influence; brain cell; cell type; in vivo; insight; intraperitoneal; member; neurosteroids; new technology; novel; positive allosteric modulator; receptor

Project Summary Many psychiatric illnesses are characterized by episodes of behavioral disruption. The current project attempts to understand the mechanisms mediating transitions between healthy and unhealthy brain and behavioral states. Stress is a major risk factor for psychiatric illnesses and is routinely employed to alter behavioral states in preclinical models. This application will utilize chronic and postpartum stress to facilitate the transition to the unhealthy network and behavioral state and investigate the mechanisms mediating these transitions. Neuroactive steroids (NAS) exert robust anxiolytic and antidepressant effects and a NAS-based treatment, brexanolone/Zulresso®, recently received FDA approval as the first antidepressant treatment for postpartum depression. This project will utilize these clinically effective NAS to investigate the impact on network and behavioral states. Our preliminary data demonstrates that chronic unpredictable stress and inappropriate postpartum stress can corrupt network activity in the basolateral amygdala (BLA) and that NAS can restore healthy network and behavioral states. Further, we demonstrate the ability of NAS to alter network activity across species, including in humans (Conte Center Overview preliminary data), highlighting the translational relevance of this approach. Despite these provocative preliminary findings, we still lack an understanding of the mechanisms mediating transitions between network and, therefore, behavioral states. The prolonged antidepressant effects of allopregnanolone are not easily explained by the known mechanism of action as positive allosteric modulators (PAMs) at GABAA receptors. In collaboration with our Conte Center collaborators and the Chemistry Core, we will investigate which of the diverse properties of NAS are capable of restoring healthy network and behavioral states with the goal of gaining a better understanding of their therapeutic properties.

项目摘要 许多精神疾病的特征是行为中断的发作。当前的项目尝试 了解健康和不健康的大脑与行为之间介导的过渡的机制 国家。压力是精神疾病的主要危险因素，通常被雇用以改变行为状态 在临床前模型中。该应用将利用慢性和产后应力来促进过渡到 不健康的网络和行为状态，并研究介导这些过渡的机制。 神经活性类固醇（NAS）发挥强大的抗焦虑和抗抑郁作用，以及基于NAS的治疗， Brexanolone/Zulresso®最近获得了FDA批准，作为产后的第一种抗抑郁药治疗 沮丧。该项目将利用这些临床上有效的NA来调查对网络的影响， 行为状态。我们的初步数据表明，慢性不可预测的压力和不适当的压力 产后压力会破坏基底外侧杏仁核（BLA）的网络活动，并且NAS可以恢复 健康的网络和行为状态。此外，我们证明了NAS改变网络活动的能力 跨物种，包括人类（孔戴中心概述初步数据），突出了翻译 这种方法的相关性。尽管这些挑衅性的初步发现，我们仍然缺乏对 机制介导网络和行为状态之间的过渡。长时间 异源性作用机理不容易解释出异源性的抗抑郁作用 GABAA受体的阳性变构调节剂（PAMS）。与我们的孔戴中心合作者合作 和化学核心，我们将研究NAS的潜水员特性能够恢复 健康的网络和行为状态，目的是更好地了解其治疗性 特性。